Abstract ! To become competent effector Th17 cells mediating the actual immune responses, T cells have to undergo two RORt-dependent differentiation processes sequentially carried out in thymus and peripheral lymphoid tissues. RORt is up-regulated in thymocyes to enhance the survival required for completion of T cell maturation process in thymus, and absence of RORt activity severely impairs thymocyte development that eventually leads to lymphoma. RORt is again up-regulated in peripheral CD4+ T cells to instruct the differentiation of Th17 cells that mediate many types of autoimmunity. RORt is thus considered an important drug target for treatment of Th17-dependent autoimmunity. However, little is known about the common and distinct mechanisms that RORt utilize to regulate these two differentiation processes. Our goal is to understand the function of RORt in both thymocytes and Th17 cells, which will facilitate to develop drugs specifically targeting Th17-dependent autoimmunity, but not interfering with thymocyte development that leads to lymphoma. The objective of this application is to understand how both thymocytes and peripheral T cells differentially use the same transcription factor RORt to regulate their differentiation processes.!